Monash University researchers report they have cracked the code behind IKAROS, an essential protein for immune cell development and protection against pathogens and cancer. The findings may reshape our comprehension of gene control networks and its impact on everything from eye color to cancer susceptibility and design of novel therapies.

The study is published in Nature Immunology in an article titled, “IKAROS and AIOLOS directly regulate AP-1 transcriptional complexes and are essential for NK cell development.”

“Ikaros transcription factors are essential for adaptive lymphocyte function, yet their role in innate lymphopoiesis is unknown,” the researchers wrote. “Using conditional genetic inactivation, we show that Ikzf1/Ikaros is essential for normal natural killer (NK) cell lymphopoiesis and IKZF1 directly represses Cish, a negative regulator of interleukin-15 receptor resulting in impaired interleukin-15 receptor signaling.”

This discovery opens the door to the prospect of potential novel cancer therapeutics. NK cells, our first line of defense against pathogens and internal threats like cancers, could be fortified by therapies enhancing their killing prowess by targeting IKAROS and JUN/FOS biology.

Nicholas Huntington, PhD, professor at Monash University’s Biomedicine Discovery Institute and the lead author of the paper noted that drugs targeting IKAROS/AIOLOS have already received approval from the FDA and local Therapeutic Goods Administration (TGA) for the treatment of B cell malignancy “but until now we haven’t understood how these drugs work. Armed with this new information it could be possible to develop novel drugs targeting these complexes which may offer differentiated pharmacology and therapeutic index for treating disease,” he said. Importantly on this front, Huntington’s team was able to show that IKAROS had a conserved role in healthy B cells and thus potentially B cell cancers.

“Collectively, we show that Ikaros family members are important regulators of apoptosis, cytokine responsiveness, and AP-1 transcriptional activity,” concluded the researchers.

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